PD-1-PD-L1 免疫检查点有助于维持自我耐受并预防自身免疫性疾病的发展。免疫检查点抑制剂是多种癌症的成功免疫疗法，但有反应的患者可能会出现免疫介导的不良事件。众所周知，PD-1 调节 CD4 和 CD8 T 细胞反应，但其在控制致病性 γδ T 细胞激活中的作用尚不清楚。在这里，我们研究了 PD-1 在实验性自身免疫性脑脊髓炎 (EAE)（多发性硬化症小鼠模型）中调节 γδ T 细胞的作用。我们发现 EAE 小鼠淋巴结 (LN) 和 CNS 中的 CD27-Vγ4 γδ T 细胞上高表达 PD-1。用抗 PD-1 治疗小鼠显着增加了 LN 和 CNS 中产生 IL-17A 的 CD27-Vγ4 γδ T 细胞，并增强了 EAE 的严重程度。抗 PD-1 对 EAE 的加剧作用在 Tcrd-/- 小鼠中消失。相反，PD-1 的连接抑制​​了经 TCR 刺激的纯化 Vγ4 γδ T 细胞的 Il17a 和 Rorc 基因表达以及 IL-17A 的产生，但不被 IL-1β 和 IL-23 刺激。我们的研究表明，PD-1 调节 TCR 激活的 CD27-Vγ4 γδ T 细胞，但细胞因子激活的 IL-17A 产生的 γδ T 细胞逃避 PD-1-PD-L1 途径的调节作用。© 2024 作者（ s）。 《欧洲免疫学杂志》由 Wiley‐VCH GmbH 出版。

The PD-1-PD-L1 immune checkpoint helps to maintain self-tolerance and prevent the development of autoimmune diseases. Immune checkpoint inhibitors are successful immunotherapeutics for several cancers, but responding patients can develop immune-mediated adverse events. It is well established that PD-1 regulates CD4 and CD8 T-cell responses, but its role in controlling the activation of pathogenic γδ T cells is less clear. Here we examined the role of PD-1 in regulating γδ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We found that PD-1 was highly expressed on CD27- Vγ4 γδ T cells in the lymph node (LN) and CNS of mice with EAE. Treatment of mice with anti-PD-1 significantly augmented IL-17A-producing CD27- Vγ4 γδ T cells in the LN and CNS and enhanced the severity of EAE. The exacerbating effect of anti-PD-1 on EAE was lost in Tcrd-/- mice. Conversely, ligation of PD-1 suppressed Il17a and Rorc gene expression and IL-17A production by purified Vγ4 γδ T cells stimulated via the TCR, but not with IL-1β and IL-23. Our study demonstrates that PD-1 regulates TCR-activated CD27- Vγ4 γδ T cells, but that cytokine-activated IL-17A producing γδ T cells escape the regulatory effects of the PD-1-PD-L1 pathway.© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.